title: The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.
abstract: This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2 -terminal Sac1-like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA. coro.paisanruiz@mssm.edu
authors.forename: Catharine E
authors.initials: CE
authors.lastname: Krebs
authors.forename: Siamak
authors.initials: S
authors.lastname: Karkheiran
authors.forename: James C
authors.initials: JC
authors.lastname: Powell
authors.forename: Mian
authors.initials: M
authors.lastname: Cao
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Hossein
authors.initials: H
authors.lastname: Darvish
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Walker
authors.forename: Gholam Ali
authors.initials: GA
authors.lastname: Shahidi
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
mesh_terms: D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000378:metabolism; D003241:Consanguinity; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000378:metabolism*; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: SYNJ1; autosomal recessive Parkinsonism; homozygosity mapping; whole-exome sequencing